The aim of this study was to explore how physical activity (PA) and energy intake (EI) changes were related to weight loss and regain following The Biggest Loser competition. At baseline, week 6 and week 30 of the competition, and 6 years after the competition, body composition was measured via dual-energy x-ray absorptiometry, resting energy expenditure was measured by using indirect calorimetry, and EI and PA were measured by using doubly labeled water. Six years after the competition, median weight loss in 14 of The Biggest Loser participants was 13%, with those maintaining a greater weight loss (meanSE) of 24.9%3.8% having increased PA by 160%23%, compared with a PA increase of 34%25% (P=0.0033) in the weight regainers who were 1.1%4.0% heavier than the precompetition baseline. EI changes were similar between weight loss maintainers and regainers (-8.7%5.6% vs. -7.4%2.7%, respectively; P=0.83). Weight regain was inversely associated with absolute changes in PA (r=-0.82; P=0.0003) but not with changes in EI (r=-0.15; P=0.61). EI and PA changes explained 93% of the individual weight loss variability at 6 years. Consistent with previous reports, large and persistent increases in PA may be required for long-term maintenance of lost weight.